Sexually dimorphic effects of estrogen receptor 2 deletion in the dorsal raphe nucleus on emotional behaviors

Sex differences in emotional behaviors and affective disorders have been widelynoted, of which sexually dimorphic secretion of gonadal steroid hormones such asestrogen is suspected to play a role. However, the underlying neural mechanismsremain poorly understood. We noted that the expression of estrogen receptor2(Esr2,orERβ), a key mediator of estrogen signaling in the brain, was enriched in thedorsal raphe nucleus (DRN), a region involved in emotion regulation. To investigatewhether DRNEsr2expression confers sex-specific susceptibility or vulnerability inemotional behaviors, we generated a conditional allele ofEsr2that allowed for site-specific deletion ofEsr2in the DRN via local injection of Cre-expressing viruses.DRN-specificEsr2deletion mildly increased anxiety behaviors in females, as shownby decreased time spent in the center zone of an open field in knockout females. Bycontrast, DRNEsr2deletion had no effects on anxiety levels in males, as demonstratedby knockout males spending comparable time in the center zone of an open field andopen arms of an elevated-plus maze. Furthermore, in the tail suspension test, DRNEsr2deletion reduced immobility, a depression-like behavior, in a male-biased manner.Together, these results reveal sex-specific functions of DRNEsr2in regulating emotionalbehaviors and suggest targeted manipulation of DRNEsr2signaling as a potential thera-peutic strategy to treat sex-biased affective disorders.